Iodinated fatty acid esters iodinated fatty acids and derivatives thereof produced by iodohydrination using alkylsilylated derivatives and alkaline iodides and the pharmacological activities thereof

ABSTRACT

Iodinated fatty acid esters, iodinated fatty acids and fluid pharmaceutical-grade stable derivatives thereof are produced by iodohydrination in an organic medium using alkylsilylated derivatives, such as trimethylsilyl chloride or trimethylchlorosilane, that react with an alkaline iodide such as sodium iodide, whereafter hydroiodic acid is formed in situ by exposure to water and the hydroiodic acid is reacted with fatty acid esters and particularly rapeseed oil fatty acid methyl esters that may be used as a biofuel for gasoline engines to provide a low-cost product, and are used therapeutically, in particular for treating goitre linked to iodine deficiency.

This application is a 371 of PCT/FR96/01075 filed Jul. 10, 1996.

BACKGROUND OF THE INVENTION

The invention relates to iodinated fatty acid esters and iodinated fattyacids and derivatives thereof obtained by iodohydrination involving theintroduction of alkylsilylated derivatives with alkaline iodides used inthe treatment of endemic goitre and pharmaceutical compositionscontaining them. They can also be used as contrast compounds inradiology and as a vehicle for chemiembolisation.

Endemic goitre is a deficiency disease which constitutes one of the mostserious problems of public health confronting the World HealthOrganisation (WHO). According to official WHO records, a thousandmillion individuals, that is 20% of the population of the world, isaffected by an iodine deficiency, mainly in developing countries (HetzelB. S., Potter B. J. and Dulberg E. M. The iodine deficiency disorders:nature, pathogenesis and epidemiology. World Rev. Nutr. Diet. 62: 59-119(1990)). Almost all of these countries are affected with very variabledegrees of prevalence. In the most severely affected regions, it ispossible to count up to 80% of subjects suffering from thyroiddysfunction: this is manifested by the appearance of unattractivehypertrophy of the glands which can develop into secondaryhypothyroidism with neurological problems. Adolescent girls and women ofchild-bearing age are most widely exposed and can give birth to a highproportion of up to 10% of newborn babies suffering from a particularform of irreversible mental disability known as endemic cretinism andconsidered as the most threatening medical and social complication.

It is universally accepted that an iodine deficiency in the diet is theprimary and predominant cause of this nutritional scourge.

The geological nature and the geographical environment therefore appearto be the main factors determining this situation although certaindietary factors are incriminated as aggravating secondary causes. Theappropriate treatment therefore involves supplementing deficientpopulations with additions of iodine covering physiologicalrequirements.

Theoretically, this objective is easy to achieve. However, experienceover recent decades has shown that the traditional vehicles for iodinesupplementation (drinking water, table salt, bread -flour) encountermajor problems in diffusion associated with the transportation, storageand consumption conditions, in (sub) tropical regions. In fact, iodineis administered in the form of sodium or potassium iodide or iodateliberating halogen in a non-storable form in adipose tissues. It istherefore necessary to take the iodinated vehicle daily for years. Thenutritional benefits are irregular and slow to obtain, and this form ofsupplementation does not allow the urgent problems encountered inregions of high prevalence to be overcome rapidly.

There is also an iodinated oil having long-lasting effect known asLipiodol® (Societe Guerbet) which, when administered in a single annualoral or parenteral dose, has demonstrated anti-goitre preventive andtherapeutic effects. This iodinated oil, designed as a contrast productin radiology, is produced from rare and relatively expensive poppy-seedoil (Somnifer papaverum). Although the high tolerance and curativeproperties of Lipiodol® have been known for a long time, this producthas not become established as a tool for massive eradication owing tothe relatively high cost with respect to the huge requirements of theThird World.

SUMMARY OF THE INVENTION

Our invention aims to overcome this handicap: a new iodinated drug isproposed which is formed from iodinated fatty acid esters or iodinatedfatty acids and derivatives thereof which are of pharmaceutical purity,stable, free of toxic contaminants, totally iodinated, have no doublebonds, are obtained by action of an alkylsilylated reagent and analkaline iodide on fatty acid esters or fatty acids and have therapeuticproperties.

For example, it is possible to produce low cost iodinated fatty acidesters from iodinated fatty acid methyl esters obtained by originalsynthesis from rapeseed oil (Brassica campestris) used as biologicalfuel in car engines having a very low cost price, and this allows masscampaigns to be envisaged. The new product allows betterbio-availability and an extended therapeutic effect because the iodineis fixed on the three fatty acids (oleic acid n-9, linoleic acid n-6 andα-linolenic acid n-3), of which the last two are essential and which areprecursors of the three main fatty acids metabolic pathways. To avoidthe risks of viral contamination through blood (hepatitis B and C, HIV),exclusively oral administration of our iodinated product is proposed.Several methods have already been described for the transformation ofunsaturated fatty acids or of unsaturated fatty acid esters in iodinatedsaturated derivatives.

DESCRIPTION OF PREFERRED EMBODIMENTS

Oleic acid can be subjected to hydrobromation followed by nucleophilicsubstitution via potassium iodide after action of hydrobromic acid (J.F. Lane and H. W. Heine: On cyclic Intermediates in SubstitutionReactions. I The Alkaline Hydrolysis of Some Aliphatic Bromoacids. J.Am. Chem. Soc. 1951, 73, 1348-1350). Olive oil cooled to the region ofthe setting point is saturated directly with hydriodic acid. Other fattyacids have been envisaged. (A. Guerbet, A. Gibaud, G. Tilly, R. Joussot,V. Loth and M. Guerbet; Monoiodostearate d'ethyle. Preparation etcaracteres analytiques. Ann. pharm. fr., 1965, 23, No. 11, 663-671).Direct iodination with hydroiodic acid is also carried out usingdehydrating substances such as polyphosphoric acids, phosphoruspentoxide (W. Kuhn, H. Hartner, F. Schindler, I. Sandner and K. Hering;German patent P 35 13 322.6/C 07 C 69/62, 1985). Hydroiodination canalso be carried out with iodine in the presence of alumina generatinghydroiodic acid (L. J. Stewart, D. Gray, R. M. Pagni and G. W. Kabalka;A Convenient Method for the addition of Hl to unsaturated hydrocarbonsusing I₂ on Al₂ O₃, Tetrahedron Lett, 1987, Vol. 28, No. 39, 4497-4498).Hydroiodination has also been carried out using the boron-N,N-diethylamine complex involving boron triiodide. (Ch. Kishan Reddy andM. Periasamy; A new, simple procedure for the generation and addition ofHl to alkenes and alkynes using Bl₃ : N, N-diethylaniline complex andacetic acid. Tetrahedron Lett., 1990, Vol. 31, No. 13, 1919-1920).Hydroiodination with potassium iodide in orthophosphoric acid can alsobe envisaged (Organic. Synthesis, Vol. 9, 66).

The document JP-A-53119817 is also known, which discloses the synthesisof glyceryl tri-(2-iodohexadecanoate) in two stages.

In the first stage, 2-bromopalmitoyl chloride is reacted with glycerinein a water-free benzene/pyridine solvent to obtain 36% of glyceryl tri-(2-bromohexadecanoate) after purification.

This is then reacted with Nal in acetone to yield 74% of glyceryltri-(2-iodohexadecanoate) after treatment with Na₂ S₂ O₃, purification,drying, etc.

As specified, among others, in German patent No. C 07 C 69/62/P 3513323.8 dated 13.4.1985 and belonging to W. Kuhn et al, the methods forthe preparation of odinated compounds lead to products containing toxicimpurities and products which are unstable in air and light during thepreparation and storage thereof. Our method of preparation leads, inparticular, to a product having various constituents and no double bondwhich is a source of instability, in particular in the presence ofoxidation derivatives and free radicals.

Iodinated fatty acid esters prepared by iodohydrination involvingalkysilylated derivatives and an alkaline iodide forming the subject ofthe invention exhibit the form of a pharmaceutically pure, stable, lightyellow, fluid, oily liquid having a relatively low cost price. The fattyacid esters used for the preparation of iodinated derivatives involvingan alkylsilylated compound and an alkaline iodide can be, for example,fatty acid triglycerides originating from vegetable oils of the rapeseedoil, poppy-seed oil, soya oil, safflower oil, groundnut oil, grapeseedoil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil,wheatgerm oil, coconut oil and palm oil type and from oils of animalorigin.

The fatty acid esters used can also be mixtures of fatty acid methylesters or ethyl esters originating form vegetable oils of the rapeseedoil, poppy-seed oil, soya oil, safflower oil, groundnut oil, grapeseedoil, sunflower oil, linseed oil, corn oil, olive oil, sesame oil,wheatgerm oil, coconut oil and palm oil type and oils of animal origin.

It is of particular interest for large-scale production of drugs to usea raw material for the synthesis of fatty acid methyl esters originatingfrom rapeseed oil used as biological fuel for car engines having a lowcost price.

Fatty acids of the oleic acid, linoleic acid, α-linolenic acid, erucicacid, arachidonic acid and ricinoleic acid type can also be used as rawmaterials.

The process for obtaining iodinated fatty acid esters or iodinated fattyacids involves reacting an alkaline iodide with an alkylsilylated halidein an organic medium giving rise, in the presence of water, tohydroiodic acid in situ reacting either with the fatty acid ester oresters or with the fatty acids.

To obtain iodinated fatty acid esters or iodinated fatty acids, forexample, sodium iodide is reacted with trimethylsilyl chloride ortrimethylchlorosilane in acetonitrile followed by the action of waterand an addition either of unsaturated fatty acid esters or ofunsaturated fatty acids.

The iodohydrination of fatty acid esters can be carried out according tothe following reaction: ##STR1## (1) fatty acid esters or fatty acids

The mode of operation, for example, for unsaturated fatty acid esters isas follows: 89.25 ml of trimethylchlorosilane (or trimethylsilylchloride) are added to a solution of 107.1 g of sodium iodide in 550 mlof acetonitrile in a nitrogen atmosphere and at 0C. 6.65 ml of water areadded dropwise after total addition of the trimethylchlorosilane. Asolution of 70 g of unsaturated fatty acid methyl or ethyl esters ofrapeseed oil is then added. After 24 hours of reaction with stirring,the reaction is then stopped with 700 ml of water. The mixture isextracted using ether. The organic phase is washed several times with a10% solution of sodium thiosulphate then several times with water. It isdried over anhydrous sodium sulphate and the ether is evaporated at 90°C. over 16 mm Hg (2133 PA) in order to eliminate the remains ofsiliceous ether. The residue is brown. The iodinated fatty acid estersdissolved in ether are then bleached over coal then filtered overalumina to eliminate the peroxides. The ether is evaporated and thetraces of solvent are eliminated using a vane pump. The mixture ofiodinated fatty acid esters obtained is golden yellow and has goodfluidity. This mixture can be identified by 1H NMR and 13C NMRspectrometry. This method of synthesis of iodinated fatty acid esterswas carried out over greater quantities. Other water-immiscible solventscan be used. The insolubility of sodium chloride in acetonitrile allowsthe total displacement of the reaction toward the formation oftrimethylsilyl iodide. This reaction is exothermic and allows thegeneration of hydrlodic acid and hydroxylated trimethylsilyl.

The secondary product SiMe₃ OH is eliminated after the iodohydrinationreaction by simple evaporation under reduced pressure and washing inwater. The iodohydrination reaction is visually followed by thebleaching (decolonization) of the solution. The sodium thiosulphateallows the elimination of the iodine present in oxidized from. In thefinal product, no NMR signal of the proton and carbon 13 NMR signalcorresponds to an ethylene system. On the other hand, no degradationproduct appears in NMR of the proton.

Characteristics of rapeseed oil iodinated fatty acid esters:

Nuclear magnetic resonance of the proton (NMR¹ H) and of the carbon 13(NMR¹³ C). An NMR¹ H spectrum of the iodinated fatty acid esters ofrapeseed oil allows the disappearance of the ethylene protons to bechecked by comparison with the spectrum of the non-iodinated fatty acidesters of rapeseed oil. Furthermore, this allows the absence of tracesof solvent diethylether and of silica ether to be checked. Moreover, anNMR¹³ C spectrum allows the disappearance of the carbons carrying thenon-saturations to be checked.

The NMR¹ H spectra obtained for several productions of iodinated fattyacid ethyl esters of rapeseed oil are identical. No spectrum reveals thepresence of diethylether or silica ether.

NMR¹ H spectrum of iodinated fatty acid ethyl esters [NMR¹ H (CDCl₃)over 200 MHz]: 0.89 ppm (3H, m, CH₃), 1.20-2.00 ppm (m, CH₂ of thechains and CH₃ CH₂ O), 2.3 ppm (2H,t,CH₂ --COOEt), 4.2 ppm (m, CHI, CH₂--OOC)

NMR¹³ C spectrum of iodinated fatty acid ethyl esters [NR³ C (CDCl₃)over 200 MHz]: 14 ppm (CH₃ at the chain end and CH₃ CH₂ O), 28-29 ppm(CHI) 22-24, 30-31, 34 ppm (CH₂ of the chains), 39-41 ppm (CH₂ --CHI),60 ppm (CH₂ --O), 173 ppm (COO).

The infrared absorption spectrum (NaCl) has the following characteristicbands: γ (C═O ester) at 1740 cm⁻¹ ; γ (saturated CH) at 2850 cm⁻¹,γ(saturated CH) at 2950 cm⁻¹

NMR¹ H spectrum of iodinated fatty acid methyl esters [(NMR¹ H (CDCl₃)over 200 MHz]: 0.89 ppm (3H, m, CH₃), 1.25-1.30 ppm (m, CH₂ of thechains, 1.60-1.80 ppm (m, CH₂) 2.3 ppm (2H,t,CH₂ --COO), 3.66 ppm (3H,s,CH₃ --OOC), 4.12 ppm (m, CHI).

NMR¹³ C spectrum of iodinated fatty acid methyl esters [NMR¹³ C (CDCl₃)over 200 MHz]: 14 ppm (CH₃ at the chain end), 28-29 ppm (CHI), 22-24,31-34 ppm (CH₂ of the chains), 38-41 ppm (CH2--CHI), 51 ppm (CH₃ --O),173 ppm (COO).

Stability: as iodinated products are generally unstable substances, itis necessary to be assured of the stability of the iodinated fatty acidesters and/or of the iodinated fatty acids. Stability is investigated byNMR¹ H, by thin film chromatography and by quantitative analysis of theiodine bound to the fatty acid esters or on the fatty acids.

NMR¹ H spectra were produced after 2 months, 3 months and 8 months ofstorage at a temperature of 20-22° C., sheltered from the light. Allthree are identical to the spectrum obtained during production. Thinfilm chromatography (silica gel plate GF 254--moving phase:diethylether/hexane 1:20--examination in ultraviolet light at 254 nm andafter atomization of a 10% m/V solution of phosphomolybdenic acid R inalcohol and heating of the plate to 120° C. for 5 min) gives observedspots of which the intensity and position are identical with regard tothe freshly prepared product and those stored for 8 months.

Stability of iodinated fatty acid esters of rapeseed oil after use intherapy on the field: the mixture of iodinated fatty acid esters ofrapeseed oil was used in investigations into patients in Africa in aregion of endemic goitre. During these investigations, the iodinatedesters were subjected to extreme conditions (transportation, exposure tolight for several hours and at temperatures of about 45° C.). After twoweeks of investigations, the iodinated fatty acid esters were analyzed:the NMR¹ H spectrum was found to be identical to that of a freshlysynthesized oil and thin layer chromatography yields spots identical tothose of freshly synthesized iodinated fatty acid esters and does notreveal a degradation product.

Test of tolerance on rats: before administering the mixture of iodinatedfatty acid esters of rapeseed oil to goitrous subjects, the tolerance ofthe mixture of iodinated esters was tested on adult male rats weighingabout 300 g. Each test group consists of 5 rats which each receive anoral administration of 0.5 ml of mixture of iodinated fatty acid estersof rapeseed oil. The rats were kept under observation. After one week,the behaviour and general state of the rats in each test group arenormal and identical to those of the control group. The iodinatedproducts prepared by the above-described method are used as generallyadministered drugs, for example as anti-goitre drugs in the pure stateor in combination with appropriate excipients in the form of a drinkableor ingestable liquid, capsules or ampoules for example. These iodinatedproducts can also be used as generally or topically administered drugs,for example as contrast products or as antiinflammatory agents inrheumatoid therapy. These products can be used as drugs which areadministered in a general or local vascular manner in the treatment ofcertain cancers by chemiembolisation involving administering ananti-cancer drug emulsioned in iodinated fatty acid esters which act ascarries for tumoral lipophilic cells.

What is claimed is:
 1. Process for obtaining at least one iodinatedfatty acid or at least one iodinated fatty acid ester or iodinatedderivatives thereof which have pharmaceutical purity, are stable andfree from toxic impurities, characterized in that it involves reactingan alkaline iodide with an alkylsilylated reagent in an organic mediumgiving rise in the presence of water to hydroiodic acid in situ reactingwith the fatty acid(s), the fatty acid ester(s) or derivatives thereofin such a way that all the double bonds initially present in the fattyacid(s) or fatty acid ester(s) or derivatives thereof are saturated iniodine in a proportion of one molecule of hydroiodic acid per doublebond.
 2. Process according to claim 1, characterized in that thealkaline iodide is sodium iodide.
 3. Process according to claim 1,characterized in that the alkylsilylated reagent is an alkylsilylatedhalide.
 4. Process according to claim 3, characterized in that thealkylsilylated halide is trimethylsilyl chloride ortrimethylchlorosilane.
 5. Process according to claim 1, characterized inthat the organic medium contains acetonitrile.
 6. Process according toclaim 1, characterized in that the fatty acid ester(s) consist(s) offatty acid triglyceride(s) originating from vegetable oil(s) selectedfrom the group formed by rapeseed oil, poppy-seed oil, soya-oil,safflower oil, groundnut oil, grapeseed oil, sunflower oil, linseed oil,corn oil, olive oil, sesame oil, wheatgerm oil, coconut oil, palm oiland oils of animal origin.
 7. Process according to claim 1,characterized in that the fatty acid ester(s) consist(s) of fatty acidmethyl ester(s) originating from vegetable oil(s) selected from thegroup formed by rapeseed oil, poppy-seed oil, soya-oil, safflower oil,groundnut oil, grapeseed oil, sunflower oil, linseed oil, corn oil,olive oil, sesame oil, wheatgerm oil, coconut oil, palm oil and oils ofanimal origin.
 8. Process according to claim 7, characterized in thatthe fatty acid ester(s) consist(s) of fatty acid methyl ester(s)originating from rapeseed oil, used as low cost price biological fuelfor car engines.
 9. Process according to claim 1, characterized in thatthe fatty acid ester(s) consist(s) of fatty acid ethyl ester(s)originating from vegetable oil(s) selected from the group formed byrapeseed oil, poppy-seed oil, soya-oil, safflower oil, groundnut oil,grapeseed oil, sunflower oil, linseed oil, corn oil, olive oil, sesameoil, wheatgerm oil, coconut oil, palm oil and oils of animal origin. 10.Process according to claim 1, characterized in that the fatty acid(s)is/are selected from the group formed by oleic acid, linoleic acid,α-linolenic acid, erucic acid, arachidonic acid and ricinoleic acid. 11.A drug comprising one of an iodinated fatty acid, iodinated fatty acidester and iodinated derivatives thereof, all double bonds initiallypresent in the one of the iodinated fatty acid, iodinated fatty acidester, and iodinated derivative thereof being saturated in iodine in aproportion of one molecule of hydroiodic acid per double bond, the drugbeing stable and free of toxic impurities and of a stabilizing reactant.12. A method for the preventive and/or therapeutic treatment of goitrecomprising administering to a patient in need of said treatment the drugof claim 11 in a pure state or in combination with excipients indrinkable or ingestable form.
 13. A method for anti-inflammatorytreatment in rheumatoid therapy comprising administering to a patient inneed of said treatment the drug of claim 11 by general or topicalmethods.
 14. A method for the treatment of cancers comprisingadministering to a patient in need of said treatment the drug of claim11 by chemiembolization.
 15. The method of claim 14, wherein theiodinated fatty acid, iodinated fatty acid ester or iodinated derivativethereof is a carrier for an anti-cancer drug emulsified in saidiodinated fatty acid, iodinated fatty acid ester or derivatives thereof,for treating tumoral lipophilic cells.
 16. A contrast product comprisingthe drug of claim
 11. 17. The drug of claim 11 comprising the iodinatedfatty acid ester that is a fatty acid triglyceride selected from thegroup of vegetable oils consisting of rapeseed oil, groundnut oil, andolive oil.
 18. The drug of claim 11 comprising the iodinated fatty acidester that is a fatty acid ethyl or methyl ester selected from the groupof oils consisting of rapeseed oil, groundnut oil, and olive oil.